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An Endoplasmic Reticulum (ER)‐Targeting DNA Nanodevice for Autophagy‐Dependent Degradation of Proteins in Membrane‐Bound Organelles

Von Wiley-VCH zur Verfügung gestellt

A new targeted protein degradation (TPD) system composed of an endoplasmic reticulum (ER)-targeting DNA nanostructure carrying protein binding ligands is developed for proteins in membrane-bound organelles. It works with the guidance of artificial membrane receptors. The targeted proteins in ERs are degraded via an autophagy-dependent pathway. This nanosystem compensates the deficiency of current TPD strategies and may contribute to future cancer therapeutics.


Targeted protein degradation via proteasomal and lysosomal pathways is a promising therapeutic approach, and proteins in cytoplasm or on the cell membrane can be easily contacted and have become the major targets. However, degradation of disease-related proteins that exist in membrane-bound organelles (MBO) such as the endoplasmic reticulum (ER) remains unsolved due to the membrane limits. Here we describe a DNA nanodevice that shows ER targeting capacity and undergoes new intracellular degradation via the autophagy-dependent pathway. Then the DNA nanostructure functionalized with specific ligands is used to selectively catch ER-localized proteins and then transport them to the lysosome for degradation. Through this technique, the degradation of both exogenous ER-resident protein (ER-eGFP) and endogenous overexpressed molecular chaperone (glucose-regulated protein 78) in cancer cells has been successfully executed with high efficiency.

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